Protocol for pathologic examination of bladder cancer according to the updates of the 5th edition of the WHO classification (2022): radical cystectomy specimens
DOI:
https://doi.org/10.14739/2310-1237.2025.1.324720Keywords:
bladder cancer, cystectomy, urothelial carcinoma, pathological reportingAbstract
Bladder cancer (BC) is the fourth most common cancer in men. Approximately a quarter of diagnosed cases of BC are characterized by the presence of invasion of the muscle layer of the organ (muscle-invasive BC), the treatment of which is usually associated with radical cystectomy. In 2022, the new 5th edition of the World Health Organization classification of tumors of the urinary system and male genital organs was presented. The new edition provides a comprehensive approach to the classification of BC, taking into account clinical, morphological and molecular genetic data.
The aim of the study is to highlight the main updates of the latest WHO classification of bladder tumors (2022) and to develop a pathology reporting standard for radical cystectomy specimens by adapting international check-lists and recommendations (CAP, ICCR).
Materials and methods. We analyzed the literature in the scientific databases PubMed and Web of Science. The following keywords were used for the search: bladder, cystectomy, pathology report, urothelial tumor, stage, molecular subgroups, WHO 2022.
Results. In this literature review, we proposed a standardized protocol for the pathologic examination of radical cystectomy specimens, taking into account the updates of the WHO classification of tumors of the urinary and male genital systems (2022) and described its components in detail.
Conclusions. Professional pathologic evaluation of BC radical cystectomy specimens is crucial for further treatment and prognosis. Knowledge of the updates of the 5th edition of the WHO tumor classification (2022) should be implemented in the daily clinical practice of a pathologist, in particular, by using the proposed pathology reporting standard for the BC radical cystectomy specimens.
References
Lopez-Beltran A, Cookson MS, Guercio BJ, Cheng L. Advances in diagnosis and treatment of bladder cancer. BMJ. 2024;384:e076743. doi: https://doi.org/10.1136/bmj-2023-076743
Ukrainian cancer registry statistics. [Cancer in Ukraine, 2022-2023. Occupation, death, demonstration of oncological service]. Bulletin of National Cancer Registry of Ukraine. 2024;25. Ukrainian. Available from: http://ncru.inf.ua/publications/BULL_25/index.htm#rubriki
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-49. doi: https://doi.org/10.3322/caac.21660
Dyrskjot L, Hansel DE, Efstathiou JA, Knowles MA, Galsky MD, Teoh J, et al. Bladder cancer. Nat Rev Dis Primers. 2023;9(1):58. doi: https://doi.org/10.1038/s41572-023-00468-9
Alfred Witjes J, Max Bruins H, Carrión A, Cathomas R, Compérat E, Efstathiou JA, et al. European Association of Urology Guidelines on Muscle-invasive and Metastatic Bladder Cancer: Summary of the 2023 Guidelines. Eur Urol. 2024;85(1):17-31. doi: https://doi.org/10.1016/j.eururo.2023.08.016.
Patel VG, Oh WK, Galsky MD. Treatment of muscle-invasive and advanced bladder cancer in 2020. CA Cancer J Clin. 2020;70(5):404-23. doi: https://doi.org/10.3322/caac.21631
Petrelli F, Coinu A, Cabiddu M, Ghilardi M, Vavassori I, Barni S. Correlation of pathologic complete response with survival after neoadjuvant chemotherapy in bladder cancer treated with cystectomy: a meta-analysis. Eur Urol. 2014;65(2):350-7. doi: https://doi.org/10.1016/j.eururo.2013.06.049
Bondarenko NS, Bondarenko OO, Polion MY, Hrytsenko PO, Shponka IS. [Protocol for pathologic examination of bladder cancer according to the updates of the 5th edition of the WHO classification (2022): biopsy and transurethral resection specimens]. Pathologia. 2024;21(3):259-70. Ukrainian. doi: https://doi.org/10.14739/2310-1237.2024.3.313797
Grignon D, Brimo F, Comperat E, Delahunt B, Koch M, Lopez-Beltran A, et al. Urinary Tract Carcinoma Histopathology Reporting Guide – Biopsy and Transurethral Resection Specimen. International Collaboration on Cancer Reporting; Sydney, Australia: International Collaboration on Cancer Reporting; 2018.
College of American Pathologists. Protocol for the Examination of Biopsy and Transurethral Resection of Bladder Tumor (TURBT) Specimens From Patients With Carcinoma of the Urinary Bladder. Version 4.2.0.0. 2023. Available from: https://documents.cap.org/protocols/Bladder.Bx.TURBT_4.2.0.0.REL_CAPCP.pdf
WHO classification of tumours: urinary and male genital tumours. 5th ed. Vol. 8. Lyon, France: IARC. 2022.
Grignon D, Brimo F, Comperat E, Delahunt B, Koch M, Lopez-Beltran A, et al. Carcinoma of the Bladder, Histopathology Reporting Guide. 1st edition. Sydney, Australia: International Collaboration on Cancer Reporting. 2018.
College of American Pathologists. Protocol for the Examination of Cystectomy Specimens From Patients With Carcinoma of the Urinary Bladder. Version 4.2.0.0. 2023. Available from: https://documents.cap.org/protocols/Bladder_4.2.0.0.REL_CAPCP.pdf
Lenis AT, Lec PM, Chamie K, MSHS M. Bladder Cancer: A Review. JAMA. 2020;324(19):1980-91. doi: https://doi.org/10.1001/jama.2020.17598
Lemos MB, Okoye E. Atlas of Surgical Pathology grossing. Cham: Springer; 2019.
Ministry of Health of Ukraine. Pro zatverdzhennia Poriadku provedennia patolohoanatomichnoho roztynu [On approval of the Procedure for conducting a pathological autopsy]. Order dated 2021 Sep 6 No. 1877 [Internet]. 2021 [cited 2025 Jan 3]. Ukrainian. Available from: https://zakon.rada.gov.ua/laws/show/z1239-21
Layton C, Bancroft JD, Suvarna SK. Fixation of tissues. In: Bancroft’s Theory and Practice of Histological Techniques. Elsevier; 2019. p. 40-63. doi: https://doi.org/10.1016/B978-0-7020-6864-5.00004-9
Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, et al. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more "personalized" approach to cancer staging: The Eighth Edition AJCC Cancer Staging Manual. CA Cancer J Clin. 2017;67(2):93-9. doi: https://doi.org/10.3322/caac.21388
Philip AT, Amin MB, Tamboli P, Lee TJ, Hill CE, Ro JY. Intravesical adipose tissue: a quantitative study of its presence and location with implications for therapy and prognosis. Am J Surg Pathol. 2000;24(9):1286-90. doi: https://doi.org/10.1097/00000478-200009000-00013
Walker NF, Gan C, Olsburgh J, Khan MS. Diagnosis and management of intradiverticular bladder tumours. Nat Rev Urol. 2014;11(7):383-90. doi: https://doi.org/10.1038/nrurol.2014.131
Tamas EF, Stephenson AJ, Campbell SC, Montague DK, Trusty DC, Hansel DE. Histopathologic features and clinical outcomes in 71 cases of bladder diverticula. Arch Pathol Lab Med. 2009;133(5):791-6. doi: https://doi.org/10.5858/133.5.791
Idrees MT, Alexander RE, Kum JB, Cheng L. The spectrum of histopathologic findings in vesical diverticulum: implications for pathogenesis and staging. Hum Pathol. 2013;44(7):1223-32. doi: https://doi.org/10.1016/j.humpath.2012.11.005
Zhong H, George S, Kauffman E, Guru K, Azabdaftari G, Xu B. Clinicopathologic characterization of intradiverticular carcinoma of urinary bladder - a study of 22 cases from a single cancer center. Diagn Pathol. 2014;9:222. doi: https://doi.org/10.1186/s13000-014-0222-8
Neuzillet Y, Comperat E, Rouprêt M, Larre S, Roy C, Quintens H, et al. Tumeurs de vessie intradiverticulaires: revue du Comité de cancérologie de l'Association française d'urologie [Intradiverticular bladder tumours: review of the Cancer Committee of the French Association of Urology]. Prog Urol. 2012;22(9):495-502. French. doi: https://doi.org/10.1016/j.purol.2012.03.008
Compérat E, Oszwald A, Wasinger G, Hansel DE, Montironi R, van der Kwast T, et al. Updated pathology reporting standards for bladder cancer: biopsies, transurethral resections and radical cystectomies. World J Urol. 2022;40(4):915-27. doi: https://doi.org/10.1007/s00345-021-03831-1
Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349(9):859-66. doi: https://doi.org/10.1056/NEJMoa022148. Erratum in: N Engl J Med. 2003;349(19):1880.
Fleischmann A, Thalmann GN, Perren A, Seiler R. Tumor regression grade of urothelial bladder cancer after neoadjuvant chemotherapy: a novel and successful strategy to predict survival. Am J Surg Pathol. 2014;38(3):325-32. doi: https://doi.org/10.1097/PAS.0000000000000142
Brimo F, Downes MR, Jamaspishvili T, Berman D, Barkan GA, Athanazio D, et al. Prognostic pathological factors in radical cystectomy after neoadjuvant chemotherapy. Histopathology. 2018;73(5):732-40. doi: https://doi.org/10.1111/his.13654
Seiler R, von Gunten M, Thalmann GN, Fleischmann A. Extracapsular extension but not the tumour burden of lymph node metastases is an independent adverse risk factor in lymph node-positive bladder cancer. Histopathology. 2011;58(4):571-8. doi: https://doi.org/10.1111/j.1365-2559.2011.03778.x
Masson-Lecomte A, Vordos D, Hoznek A, Yiou R, Allory Y, Abbou CC, et al. External validation of extranodal extension and lymph node density as predictors of survival in node-positive bladder cancer after radical cystectomy. Ann Surg Oncol. 2013;20(4):1389-94. doi: https://doi.org/10.1245/s10434-012-2753-0
Fajkovic H, Cha EK, Jeldres C, Robinson BD, Rink M, Xylinas E, et al. Extranodal extension is a powerful prognostic factor in bladder cancer patients with lymph node metastasis. Eur Urol. 2013;64(5):837-45. doi: https://doi.org/10.1016/j.eururo.2012.07.026
Fritsche HM, May M, Denzinger S, Otto W, Siegert S, Giedl C, et al. Prognostic value of perinodal lymphovascular invasion following radical cystectomy for lymph node-positive urothelial carcinoma. Eur Urol. 2013;63(4):739-44. doi: https://doi.org/10.1016/j.eururo.2012.09.053
Kimura S, Mari A, Foerster B, Abufaraj M, Vartolomei MD, Stangl-Kremser J, et al. Prognostic Value of Concomitant Carcinoma In Situ in the Radical Cystectomy Specimen: A Systematic Review and Meta-Analysis. J Urol. 2019;201(1):46-53. doi: https://doi.org/10.1016/j.juro.2018.05.162
Martin-Doyle W, Leow JJ, Orsola A, Chang SL, Bellmunt J. Improving selection criteria for early cystectomy in high-grade t1 bladder cancer: a meta-analysis of 15,215 patients. J Clin Oncol. 2015;33(6):643-50. doi: https://doi.org/10.1200/JCO.2014.57.6967
Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;515(7528):558-62. doi: https://doi.org/10.1038/nature13904
Witjes JA, Babjuk M, Bellmunt J, Bruins HM, De Reijke TM, De Santis M, et al. Corrigendum to 'EAU-ESMO Consensus Statements on the Management of Advanced and Variant Bladder Cancer-An International Collaborative Multistakeholder Effort Under the Auspices of the EAU-ESMO Guidelines Committees' [European Urology 77 (2020) 223-250]. Eur Urol. 2020;78(1):e48-e50. doi: https://doi.org/10.1016/j.eururo.2020.03.017. Erratum for: Eur Urol. 2020;77(2):223-50. doi: https://doi.org/10.1016/j.eururo.2019.09.035
"Державний реєстр лікарських засобів України". Інформаційний фонд. [Електронний ресурс]. Режим доступу до ресурсу: http://www.drlz.com.ua. Дата звернення: 27.06.2024.
Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909-20. doi: https://doi.org/10.1016/S0140-6736(16)00561-4
European Medicines Agency. EMA restricts use of Keytruda and Tecentriq in bladder cancer. Press release 2018 Jun 1. Available from: https://www.ema.europa.eu/en/news/ema-restricts-use-keytruda-tecentriq-bladder-cancer
Reis H, Serrette R, Posada J, Lu V, Chen YB, Gopalan A, et al. PD-L1 Expression in Urothelial Carcinoma With Predominant or Pure Variant Histology: Concordance Among 3 Commonly Used and Commercially Available Antibodies. Am J Surg Pathol. 2019;43(7):920-7. doi: https://doi.org/10.1097/PAS.0000000000001264
Eckstein M, Erben P, Kriegmair MC, Worst TS, Weiß CA, Wirtz RM, et al. Performance of the Food and Drug Administration/EMA-approved programmed cell death ligand-1 assays in urothelial carcinoma with emphasis on therapy stratification for first-line use of atezolizumab and pembrolizumab. Eur J Cancer. 2019;106:234-43. doi: https://doi.org/10.1016/j.ejca.2018.11.007
Tretiakova M, Fulton R, Kocherginsky M, Long T, Ussakli C, Antic T, et al. Concordance study of PD-L1 expression in primary and metastatic bladder carcinomas: comparison of four commonly used antibodies and RNA expression. Mod Pathol. 2018;31(4):623-32. doi: https://doi.org/10.1038/modpathol.2017.188
Eckstein M, Cimadamore A, Hartmann A, Lopez-Beltran A, Cheng L, Scarpelli M, et al. PD-L1 assessment in urothelial carcinoma: a practical approach. Ann Transl Med. 2019;7(22):690. doi: https://doi.org/10.21037/atm.2019.10.24
Zhou H, Guo CC, Ro JY. Urinary Bladder Pathology. 1st ed. Springer; 2021.
Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554(7693):544-8. doi: https://doi.org/10.1038/nature25501
Wang L, Saci A, Szabo PM, Chasalow SD, Castillo-Martin M, Domingo-Domenech J, et al. EMT- and stroma-related gene expression and resistance to PD-1 blockade in urothelial cancer. Nat Commun. 2018;9(1):3503. doi: https://doi.org/10.1038/s41467-018-05992-x
Kamoun A, de Reyniès A, Allory Y, Sjödahl G, Robertson AG, Seiler R, et al. A Consensus Molecular Classification of Muscle-invasive Bladder Cancer. Eur Urol. 2020;77(4):420-33. doi: https://doi.org/10.1016/j.eururo.2019.09.006
Van Allen EM, Mouw KW, Kim P, Iyer G, Wagle N, Al-Ahmadie H, et al. Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma. Cancer Discov. 2014;4(10):1140-53. doi: https://doi.org/10.1158/2159-8290.CD-14-0623
Iyer G, Balar AV, Milowsky MI, Bochner BH, Dalbagni G, Donat SM, et al. Multicenter Prospective Phase II Trial of Neoadjuvant Dose-Dense Gemcitabine Plus Cisplatin in Patients With Muscle-Invasive Bladder Cancer. J Clin Oncol. 2018;36(19):1949-56. doi: https://doi.org/10.1200/JCO.2017.75.0158
Pal SK, Rosenberg JE, Hoffman-Censits JH, Berger R, Quinn DI, Galsky MD, et al. Efficacy of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Inhibitor, in Patients with Previously Treated Advanced Urothelial Carcinoma with FGFR3 Alterations. Cancer Discov. 2018;8(7):812-21. doi: https://doi.org/10.1158/2159-8290.CD-18-0229
Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, et al. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2019;381(4):338-48. doi: https://doi.org/10.1056/NEJMoa1817323
Dadhania V, Zhang M, Zhang L, Bondaruk J, Majewski T, Siefker-Radtke A, et al. Meta-Analysis of the Luminal and Basal Subtypes of Bladder Cancer and the Identification of Signature Immunohistochemical Markers for Clinical Use. EBioMedicine. 2016;12:105-17. doi: https://doi.org/10.1016/j.ebiom.2016.08.036
Guo CC, Bondaruk J, Yao H, Wang Z, Zhang L, Lee S, et al. Assessment of Luminal and Basal Phenotypes in Bladder Cancer. Sci Rep. 2020;10(1):9743. doi: https://doi.org/10.1038/s41598-020-66747-7
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